Age is a significant risk factor in vulnerability to cognitive decline associated with infection, surgery, heart attack and psychological stress. The cognitive function of previously normal older people is more likely to be seriously impaired if they experience one of these physiological or psychological stressors. The mechanisms that mediate this vulnerability are largely unknown. In this exploratory project, we will use a rodent model of aging-associated cognitive vulnerability to infection to examine the hypothesis that the combined effects of aging and infection will significantly decrease BDNF and BDNF-dependent synaptic plasticity in the hippocampus. We hypothesize that aging sensitizes the hippocampal inflammatory response to peripheral infection, increasing the magnitude and the duration of the increase in brain IL-1, thus prolonging its suppression of BDNF-dependent processes. In this proposal, we outline experiments (Specific Aim 1) to examine basal synaptic transmission and short-lasting forms of synaptic plasticity in hippocampal slices taken from young and aged rats, with and without recent exposure to an immune challenge. In Specific Aim 2, we will examine several forms of long-lasting synaptic plasticity in the hippocampal slices. In doing so, we will test the hypothesis that the memory deficits observed in the aged animals following infection, which are specific to long-lasting forms of memory, will be mirrored by specific deficits in long-lasting synaptic plasticity. We will also be able to test the hypothesis that forms of long-lasting synaptic plasticity that are BDNF-dependent will be particularly compromised by the combined effects of aging and infection. These proposed experiments will provide the basis for further investigation of the cellular and molecular processes giving rise to aging-associated increases in vulnerability to cognitive decline, and may ultimately provide strategies for improving cognitive resiliency. PUBLIC HEALTH RELEVANCE The cognitive abilities of older people are more vulnerable to the deleterious effects of challenging life events including surgery, infection and psychological stress than those of younger people, but very little is known about the mechanisms that mediate this vulnerability. The experiments proposed here are designed to explore the brain mechanisms involved, using a rodent model that closely mimics the age-associated increases in cognitive vulnerability to infection. Specifically, we plan to determine if infection-evoked deficits in memory in aged animals are associated with specific deficits in synaptic function/plasticity.